Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies

Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):E3268-77. doi: 10.1073/pnas.1217207109. Epub 2012 Oct 30.

Abstract

Broadly neutralizing HIV antibodies (bNAbs) can recognize carbohydrate-dependent epitopes on gp120. In contrast to previously characterized glycan-dependent bNAbs that recognize high-mannose N-glycans, PGT121 binds complex-type N-glycans in glycan microarrays. We isolated the B-cell clone encoding PGT121, which segregates into PGT121-like and 10-1074-like groups distinguished by sequence, binding affinity, carbohydrate recognition, and neutralizing activity. Group 10-1074 exhibits remarkable potency and breadth but no detectable binding to protein-free glycans. Crystal structures of unliganded PGT121, 10-1074, and their likely germ-line precursor reveal that differential carbohydrate recognition maps to a cleft between complementarity determining region (CDR)H2 and CDRH3. This cleft was occupied by a complex-type N-glycan in a "liganded" PGT121 structure. Swapping glycan contact residues between PGT121 and 10-1074 confirmed their importance for neutralization. Although PGT121 binds complex-type N-glycans, PGT121 recognized high-mannose-only HIV envelopes in isolation and on virions. As HIV envelopes exhibit varying proportions of high-mannose- and complex-type N-glycans, these results suggest promiscuous carbohydrate interactions, an advantageous adaptation ensuring neutralization of all viruses within a given strain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology*
  • Clone Cells
  • Crystallography, X-Ray
  • Epitopes / immunology
  • HIV Antibodies / chemistry
  • HIV Antibodies / immunology*
  • HIV-1 / immunology
  • Humans
  • Immunoglobulin Fab Fragments / chemistry
  • Immunoglobulin Fab Fragments / immunology
  • Leukocytes, Mononuclear / immunology
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Mutant Proteins / metabolism
  • Neutralization Tests
  • Polysaccharides / chemistry
  • Polysaccharides / immunology*
  • Protein Binding

Substances

  • Antibodies, Neutralizing
  • Epitopes
  • HIV Antibodies
  • Immunoglobulin Fab Fragments
  • Ligands
  • Mutant Proteins
  • Polysaccharides

Associated data

  • PDB/4FQ1
  • PDB/4FQ2
  • PDB/4FQC
  • PDB/4FQQ